The Glasgow Microenvironment Score: an exemplar of contemporary biomarker evolution in colorectal cancer.

Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar stage disease. Molecular profiling has highlighted the heterogeneity of colorectal cancer but has had limited impact in daily clinical practice. Biomarkers with robust prognostic and therapeutic relevance are urgently required. Ideally, biomarkers would be derived from H&E sections used for routine pathological staging, have reliable sensitivity and specificity, and require minimal additional training. The biomarker targets would capture key pathological features with proven additive prognostic and clinical utility, such as the local inflammatory response and tumour microenvironment. The Glasgow Microenvironment Score (GMS), first described in 2014, combines assessment of peritumoural inflammation at the invasive margin with quantification of tumour stromal content. Using H&E sections, the Klintrup-Mäkinen (KM) grade is determined by qualitative morphological assessment of the peritumoural lymphocytic infiltrate at the invasive margin and tumour stroma percentage (TSP) calculated in a semi-quantitative manner as a percentage of stroma within the visible field. The resulting three prognostic categories have direct clinical relevance: GMS 0 denotes a tumour with a dense inflammatory infiltrate/high KM grade at the invasive margin and improved survival; GMS 1 represents weak inflammatory response and low TSP associated with intermediate survival; and GMS 2 tumours are typified by a weak inflammatory response, high TSP, and inferior survival. The prognostic capacity of the GMS has been widely validated while its potential to guide chemotherapy has been demonstrated in a large phase 3 trial cohort. Here, we detail its journey from conception through validation to clinical translation and outline the future for this promising and practical biomarker.

Sarcopenia is independently associated with poor preoperative physical fitness in patients undergoing colorectal cancer surgery.

BACKGROUND: Accurate preoperative risk assessment for major colorectal cancer (CRC) surgery remains challenging. Body composition (BC) and cardiopulmonary exercise testing (CPET) can be used to evaluate risk. The relationship between BC and CPET in patients undergoing curative CRC surgery is unclear. METHODS: Consecutive patients undergoing CPET prior to CRC surgery between 2010 and 2020 were identified between two different UK hospitals. Body composition phenotypes such as sarcopenia, myosteatosis, and visceral obesity were defined using widely accepted thresholds using preoperative single axial slice CT image at L3 vertebrae. Relationships between clinicopathological, BC, and CPET variables were investigated using linear regression analysis. RESULTS: Two hundred eighteen patients with stage I-III CRC were included. The prevalence of sarcopenia, myosteatosis, and visceral obesity was 62%, 33%, and 64%, respectively. The median oxygen uptake at anaerobic threshold (VO2 at AT) was 12.2 mL/kg/min (IQR 10.6-14.2), and oxygen uptake at peak exercise (VO2 peak) was 18.8 mL/kg/min (IQR 15.4-23). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 at AT. While ASA grade (P < 0.001) and BMI (P = 0.007) were negatively associated with VO2 at AT, on multivariate linear regression analysis, these variables remained significant (P < 0.05). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 peak, whereas age (P < 0.001), ASA grade (P < 0.001), BMI (P = 0.003), sarcopenia (P = 0.015), and myosteatosis (P < 0.001) were negatively associated with VO2 peak. On multivariate linear regression analysis age (P < 0.001), ASA grade (P < 0.001), BMI (P < 0.001), and sarcopenia (P = 0.006) were independently and negatively associated with VO2 peak. CONCLUSIONS: The novel finding that sarcopenia is independently associated with reduced VO2 peak performance in CPET supports the supposition that reduced muscle mass relates to poor physical function in CRC patients. Further work should be undertaken to assess whether sarcopenia diagnosed on CT can act as suitable surrogate for CPET to further enhance personalized risk stratification.

The relationship between LDH and GLIM criteria for cancer cachexia: Systematic review and meta-analysis.

INTRODUCTION: Cancer cachexia is a clinical condition characterized by recognizable "sickness behaviors" accompanied by loss of lean body tissue. The Global Leadership on Malnutrition (GLIM) has proposed phenotypic (unintentional weight loss, low body mass index and low muscle mass) and aetiologic (reduced food intake and inflammation or disease burden) diagnostic criteria. Recent work has suggested serum lactate dehydrogenase (LDH) might represent a 3rd aetiologic criteria. Little is known of its relationship with GLIM. A systematic review and meta-analysis of their comparative prognostic value and association was performed. METHODS: A search of electronic databases (PubMed, Medline, Ovid, Cochrane) up to February 2023 was used to identify studies that compared the prognostic value of LDH and components of the GLIM criteria in cancer. An analysis of the relationship between LDH and the components of GLIM was undertaken where this data was available. RevMan 5.4.1 was used to perform a meta-analysis for each diagnostic criteria that had 3 or more studies which reported hazard ratios with a 95 per cent confidence interval for overall survival (OS). RESULTS: A total of 119 studies were reviewed. Advanced lung cancer was the most studied population. Included in the meta-analysis were 6 studies (n=2165) on LDH and weight loss, 17 studies (n=7540) on LDH and low BMI, 5 studies (n=758) on LDH and low muscle mass, 0 studies on LDH and food intake and 93 studies (n=32,190) on LDH and inflammation. There was a significant association between elevated serum LDH and each of low BMI (OR 1.39, 1.09 - 1.77; p=0.008), elevated NLR (OR 2.04, 1.57 - 2.65; p<0.00001) and elevated CRP (OR 2.58, 1.81 - 3.67; p<0.00001). There was no association between elevated serum LDH and low muscle mass. Only one study presented data on the association between LDH and unintentional weight loss. Elevated LDH showed a comparative OS (HR 1.86, 1.57 - 2.07; p<0.00001) to unintentional weight loss (HR 1.57, 1.23 - 1.99; p=0.0002) and had a similar OS (HR 2.00, 1.70 - 2.34; p<0.00001) to low BMI (HR 1.57, 1.29-2.90; p<0.0001). LDH also showed an OS (HR 2.25, 1.76 - 2.87; p<0.00001) congruous with low muscle mass (HR 1.93, 1.14 - 3.27; p=0.01) and again, LDH conferred as poor an OS (HR 1.77, 1.64-1.90; p<0.00001) as elevated NLR (HR 1.61, 1.48 - 1.77; p<0.00001) or CRP (HR 1.55, 1.43 - 1.69; p<0.00001). CONCLUSION: Current literature suggests elevated serum LDH is associated with inflammation in cancer (an aetiologic GLIM criterion), however more work is required to establish the relationship between LDH and the phenotypic components of GLIM. Additionally, elevated serum LDH appears to be a comparative prognosticator of overall survival in cancer when compared to the GLIM criteria.

Cardiopulmonary exercise testing, computed tomography-derived body composition, systemic inflammation and survival after elective abdominal aortic aneurysm repair: A retrospective cohort study.

BACKGROUND: Cardio-pulmonary exercise testing (CPEX) is selectively used before intervention for abdominal aortic aneurysm (AAA). Sarcopenia, a chronic condition defined by reduced skeletal muscle function and volume, can be assessed radiologically by computed tomography (CT)-derived body composition analysis (CT-BC), and is associated with systemic inflammation. OBJECTIVE: The aim was to describe the association between CT-BC, CPEX, inflammation and survival in patients undergoing elective intervention for AAA. SETTING: Patients were recruited retrospectively from a single, secondary-care centre-operative database. Cases undergoing elective endovascular aneurysm repair (EVAR) and open surgical repair (OSR) between 31 March 2015 and 25 June 2020 were included. PATIENTS: There were 176 patients (130 EVAR, 46 OSR) available for analysis in the final study; median (interquartile range [IQR]) follow-up was 60.5 [27] months, and all completed a minimum of 2 years follow-up. MAIN OUTCOME MEASURES: Preoperative CPEX tests were recorded. CT sarcopenia score [CT-SS, range 0 to 2, calculated based on normal/low SMI (0/1) and normal/low SMD (0/1)] assessed radiological sarcopenia. Preoperative modified Glasgow Prognostic score (mGPS) was used to assess systemic inflammation. RESULTS: Mean [95% confidence interval (CI) survival in the CT-SS 0 vs. CT-SS 1 vs. CT-SS 2 subgroups was 80.1 (73.6 to 86.6) months vs. 70.3 (63.5 to 77.1) months vs. 63.8 (53.4 to 74.2) months] ( P  = 0.01). CT-SS was not associated with CPEX results ( P  > 0.05). Elevated CT-SS [hazard ratio (HR) 1.83, 95% CI, 1.16 to 2.89, P  < 0.01] was independently associated with increased hazard of long-term mortality; however, CPEX results were not ( P  > 0.05). CONCLUSION: CPEX test results were not consistently associated with body composition and did not have significant prognostic value in patients undergoing elective treatment for AAA.

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer.

Colorectal cancer (CRC) is a heterogenous malignancy and research is focused on identifying novel ways to subtype patients. In this study, a novel classification system, tumour microenvironment score (TMS), was devised based on Klintrup-Mäkinen grade (KMG), tumour stroma percentage (TSP), and tumour budding. TMS was performed using a haematoxylin and eosin (H&E)-stained section from retrospective CRC discovery and validation cohorts (n = 1,030, n = 787). TMS0 patients had high KMG, TMS1 were low for KMG, TSP, and budding, TMS2 were high for budding, or TSP and TMS3 were high for TSP and budding. Scores were assessed for association with survival and clinicopathological characteristics. Mutational landscaping and Templated Oligo-Sequencing (TempO-Seq) profiling were performed to establish differences in the underlying biology of TMS. TMS was independently prognostic in both cohorts (p < 0.001, p < 0.001), with TMS3 predictive of the shortest survival times. TMS3 was associated with adverse clinical features including sidedness, local and distant recurrence, higher T stage, higher N stage, and presence of margin involvement. Gene set enrichment analysis of TempO-Seq data showed higher expression of genes associated with hallmarks of cancer pathways including epithelial to mesenchymal transition (p < 0.001), IL2 STAT5 signalling (p = 0.007), and angiogenesis (p = 0.017) in TMS3. Additionally, enrichment of immunosuppressive immune signatures was associated with TMS3 classification. In conclusion, TMS represents a novel and clinically relevant method for subtyping CRC patients from a single H&E-stained tumour section.

A systematic review of the neutrophil to lymphocyte and platelet to lymphocyte ratios in patients with lower extremity arterial disease.

Lower extremity arterial disease (LEAD) is caused by atherosclerotic plaque in the arterial supply to the lower limbs. The neutrophil to lymphocyte and platelet to lymphocyte ratios (NLR, PLR) are established markers of systemic inflammation which are related to inferior outcomes in multiple clinical conditions, though remain poorly described in patients with LEAD. This review was carried out in accordance with PRISMA guidelines. The MEDLINE database was interrogated for relevant studies. Primary outcome was the prognostic effect of NLR and PLR on clinical outcomes following treatment, and secondary outcomes were the prognostic effect of NLR and PLR on disease severity and technical success following revascularisation. There were 34 studies included in the final review reporting outcomes on a total of 19870 patients. NLR was investigated in 21 studies, PLR was investigated in two studies, and both NLR & PLR were investigated in 11 studies. Relating to increased levels of systemic inflammation, 20 studies (100%) reported inferior clinical outcomes, 13 (92.9%) studies reported increased disease severity, and seven (87.5%) studies reported inferior technical results from revascularisation. The studies included in this review support the role of elevated NLR and PLR as key components influencing the clinical outcomes, severity, and success of treatment in patients with LEAD. The use of these easily accessible, cost effective and routinely available markers is supported by the present review.

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes.

Neoadjuvant radiotherapy (RT) is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitising rectal tumours to RT to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer.

CT-derived body composition: Differential association with disease, age and inflammation in a retrospective cohort study.

BACKGROUND: Low skeletal muscle mass and density, as assessed by CT-body composition (CT-BC), are recognised to have prognostic value in non-cancer and cancer patients. The aim of the present study was to compare CT-BC parameters between non-cancer (abdominal aortic aneurysm, AAA) and cancer (colorectal cancer, CRC) patients. METHODS: Two retrospective multicentre cohorts were compared. Thresholds of visceral fat area (VFA, Doyle), skeletal fat index (SFI, Ebadi), skeletal muscle index (SMI, Martin), and skeletal muscle density (SMD, Martin) were applied to these cohorts and compared. The systemic inflammatory response (SIR) was measured by the systemic inflammatory grade (SIG). RESULTS: 1695 patients were included; 759 patients with AAA and 936 patients with CRC. Low SMD (33% vs. 66%, p <0.001) was more prevalent in the CRC cohort. Low SMI prevalence was similar in both cohorts (51% vs. 51%, p = 0.80). Compared with the AAA cohort, the CRC cohort had a higher prevalence of raised SIG (p <0.001). Increasing age (OR 1.54, 95% CI 1.38-1.72, p < 0.001) and elevated SIG (OR 1.23, 95% CI 1.09-1.40, p = 0.001) were independently associated with increased odds of low SMI. Increasing age (OR 1.90, 95% CI 1.66-2.17, p < 0.001) CRC diagnosis (OR 5.89, 95% CI 4.55-7.62, p < 0.001), ASA > 2 (OR 1.37, 95% CI 1.08-1.73, p = 0.01), and elevated SIG (OR 1.19, 95% CI 1.03-1.37, p = 0.02) were independently associated with increased odds of low SMD. CONCLUSIONS: Increasing age and systemic inflammation appear to be important determinants of loss of skeletal muscle mass and quality irrespective of disease.

Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study.

INTRODUCTION: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. METHODS: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. RESULTS: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). CONCLUSIONS: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Radiation-induced changes in gene expression in rectal cancer specimens.

PURPOSE: The standard-of-care for locally advanced rectal cancer is radiotherapy-based neoadjuvant therapy followed by surgical resection. This article reviews the evidence of molecular changes at the transcriptome level induced through radiotherapy in rectal cancer. METHODS: The PubMed search "(radiation OR radiotherapy) cancer (transcriptome OR "gene expression") rectal" was used. The studies taken forward utilised gene-expression data on both pre-treatment and post-treatment rectal adenocarcinoma biospecimens from patients treated with RT-based neoadjuvant strategies. RESULTS: Twelve publications met the review criteria. There was variation in approaches in terms of design, patient population, cohort size, timing of the post-radiotherapy sampling and method of measuring gene expression. Most of the post-treatment biospecimen retrievals were at resection. The literature indicates a broad upregulation of immune activity through radiotherapy using gene-expression data. CONCLUSION: Future studies would benefit from standardised prospective approaches to sampling to enable the inclusion of timepoints relevant to the tumour and immune response.

A Review of Scheduling Strategies for Radiotherapy and Immune Checkpoint Inhibition in Locally Advanced Rectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy across the globe and, despite advances in treatment strategies, survival rates remain low. Rectal cancer (RC) accounts for most of these cases, and traditional management strategies for advanced disease include total neoadjuvant therapy (TNT) with chemoradiotherapy followed by curative surgery. Unfortunately, approximately 10-15% of patients have no response to treatment or have recurrence at a short interval following radiotherapy. The introduction of immunotherapy in the form of immune checkpoint blockade (ICB) in metastatic colorectal cancer has improved clinical outcomes, yet most patients with RC present with microsatellite stable disease, which lacks the immune-rich microenvironment where ICB is most effective. There is evidence that combining radiotherapy with ICB can unlock the mechanisms that drive resistance in patients; however, the sequencing of these therapies is still debated. This review offers a comprehensive overview of clinical trials and preclinical models that use radiotherapy-immunotherapy combinations in RC in an attempt to extrapolate the ideal sequencing of the two treatment modalities. The results highlight the dearth of evidence to answer the question of whether ICB should be given before, during, or after radiotherapy, yet it is suggested that improving the relevance of our preclinical models will provide a platform with higher translational value and will lead to appropriate clinical trial designs.

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

Effect of differing flap reconstruction strategies in perineal closure following advanced pelvic oncological resection: a retrospective cohort study.

INTRODUCTION: Advancing approaches to locally invasive pelvic malignancy creates a large tissue defect resulting in perineal wound complications, dehiscence, and perineal hernia. Use of reconstructive flaps such as vertical rectus abdominus myocutaneous (VRAM) flap, gracilis, anterolateral thigh and gluteal flaps have been utilised in our institution to address perineal closure. The authors compared outcomes using different flap techniques along with primary perineal closure in advanced pelvic oncological resection. METHODS: A prospectively maintained database of patients undergoing advanced pelvic oncological resection in a single tertiary hospital was retrospectively analysed. This study included consecutive patients between 2014 and 2021 according to the Strengthening The Reporting of Cohort Studies in Surgery (STROCSS) criteria. Primary outcome measures were the frequency of postoperative perineal complications between primary closure, VRAM, gluteal and thigh (anterolateral thigh and gracilis) reconstruction. RESULTS: One hundred twenty-two patients underwent advanced pelvic resection with perineal closure. Of these, 40 patients underwent extra-levator abdominoperineal resection, and 70 patients underwent pelvic exenteration. Sixty-four patients received reconstructive flap closure, which included VRAM (22), gluteal (21) and thigh flaps (19). Perineal infection and dehiscence rates were low. Infection rates were lower in the flap group despite a higher rate of radiotherapy ( P <0.050). Reoperation rates were infrequent (<10%) but specific for each flap, such as donor-site hernia following VRAM and flap dehiscence after thigh flap reconstruction. CONCLUSIONS: In patients who are at high risk of postoperative perineal infections, reconstructive flap closure offers acceptable outcomes. VRAM, gluteal and thigh flaps offer comparable outcomes and can be tailored to the individual patient.

Pathological determinants of outcome following resection of locally advanced or locally recurrent rectal cancer.

INTRODUCTION: Pathological factors that influence and predict survival following pelvic exenteration (PE) for locally advanced (LARC) or locally recurrent rectal cancer (LRRC), especially LRRC, remain poorly understood. A clear resection margin has previously been demonstrated to be of most significance. MATERIALS AND METHODS: A retrospective cohort study was performed for all patients undergoing a curative PE for LARC or LRRC between 2008 and 2021 at a tertiary referral UK specialist colorectal hospital. Cox regression analysis was planned to identify pathological factors associated with overall (OS), disease free (DFS) and local recurrence free survival (LRFS). RESULTS: 388 patients were included in the analysis with 256 resections for LARC and 132 for LRRC. 62.4% of patients were male with a median age of 59 years (IQR 49-67). 247 (64%) partial pelvic exenterations and 141 (36%) total pelvic exenterations performed. Overall R0 rate 86.6%. Poorly differentiated tumours and a positive resection margin independently influenced OS, DFS and LRFS on multivariate analysis in LARC. On multivariate analysis venous invasion negatively influenced DFS and poorly differentiated lesions negatively influenced LRFS in LRRC. CONCLUSIONS: A positive resection margin and poorly differentiated tumours are significant negative prognostic markers for survival and recurrence in LARC. The results of this study support the need to look for alternative prognostic markers beyond that in the existing standard reporting dataset for rectal cancers. With increasing R0 rates, novel prognostic pathological markers are required to help guide treatment and surveillance for patients with LRRC.

The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

The relationship between computed tomography-derived body composition, systemic inflammation, and survival in patients with abdominal aortic aneurysm.

OBJECTIVE: Patient selection and risk stratification for elective repair of abdominal aortic aneurysm (AAA), either by open surgical repair or by endovascular aneurysm repair, remain challenging. Computed tomography (CT)-derived body composition analysis (CT-BC) and systemic inflammation-based scoring systems such as the systemic inflammatory grade (SIG) appear to offer prognostic value in patients with AAA undergoing endovascular aneurysm repair. The relationship between CT-BC, systemic inflammation, and prognosis has been explored in patients with cancer, but data in noncancer populations are lacking. The present study aimed to examine the relationship between CT-BC, SIG, and survival in patients undergoing elective intervention for AAA. METHODS: A total of 611 consecutive patients who underwent elective intervention for AAA at three large tertiary referral centers were retrospectively recruited for inclusion into the study. CT-BC was performed and analyzed using the CT-derived sarcopenia score (CT-SS). Subcutaneous and visceral fat indices were also recorded. SIG was calculated from preoperative blood tests. The outcomes of interest were overall and 5-year mortality. RESULTS: Median (interquartile range) follow-up was 67.0 (32) months, and there were 194 (32%) deaths during the follow-up period. There were 122 (20%) open surgical repair cases, 558 (91%) patients were male, and the median (interquartile range) age was 73.0 (11.0) years. Age (hazard ratio [HR]: 1.66, 95% confidence interval [CI]: 1.28-2.14, P < .001), elevated CT-SS (HR: 1.58, 95% CI: 1.28-1.94, P < .001), and elevated SIG (HR: 1.29, 95% CI: 1.07-1.55, P < .01) were independently associated with increased hazard of mortality. Mean (95% CI) survival in the CT-SS 0 and SIG 0 subgroup was 92.6 (84.8-100.4) months compared with 44.9 (30.6-59.2) months in the CT-SS 2 and SIG ≥2 subgroup (P < .001). Patients with CT-SS 0 and SIG 0 had 90% (standard error: 4%) 5-year survival compared with 34% (standard error: 9%) in patients with CT-SS 2 and SIG ≥2 (P < .001). CONCLUSIONS: Combining measures of radiological sarcopenia and the systemic inflammatory response offers prognostic value in patients undergoing elective intervention for AAA and may contribute to future clinical risk predication strategies.

The Relationship between Clinical Frailty Score, CT-Derived Body Composition, Systemic Inflammation, and Survival in Patients with Chronic Limb-Threatening Ischemia.

BACKGROUND: Frailty is a chronic condition with complex etiology and impaired functional performance that has been associated with altered body composition and chronic inflammation. Chronic limb-threatening ischemia (CLTI) carries significant morbidity and mortality and is associated with poor quality of life. The present study aims to examine these relationships and their prognostic value in patients with CLTI. METHODS: Consecutive patients presenting as unscheduled admissions to a single tertiary center with CLTI were included over a 12-month period. Frailty was diagnosed using the Clinical Frailty Scale (CFS). Body composition was assessed using computerised tomography (CT) at the L3 vertebral level (CT-BC) to generate visceral and subcutaneous fat indices, skeletal muscle index, and skeletal muscle density. Skeletal muscle index and skeletal muscle density were combined to form the CT-sarcopenia score (CT-SS). Systemic inflammation was assessed by the modified Glasgow prognostic score (mGPS). The primary outcome was overall mortality. RESULTS: There were 190 patients included with a median (interquartile range) follow-up of 22 (6) months (range 15-32 months) and 79 deaths during the follow-up period. One hundred patients (53%) had a CFS >4. CFS >4 (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.25-3.66, P < 0.01), CT-SS (HR 1.47, 95% CI 1.03-2.09, P < 0.05), and mGPS (HR 1.54, 95% CI 1.11-2.13, P < 0.01) were independently associated with increased mortality. CT-SS (odds ratio 1.88, 95% CI 1.09-3.24, P < 0.01) was independently associated with CFS >4. Patients with CT-SS 0 and CFS ≤4 had 90% (standard error [SE] 5%) 1-year survival, compared with 35% (SE 9%) in patients with CT-SS 2 and CFS >4 (P < 0.001). Patients with mGPS 0 and CFS ≤4 had 94% (SE 4%) 1-year survival compared with 44% (SE 6%) in the mGPS 2 and CFS >4 subgroup (P < 0.001). CONCLUSIONS: Frailty assessed by CFS was associated with CT-BC. CFS, CT-SS, and mGPS were associated with poorer survival in patients presenting as unscheduled admissions with CLTI. CT-SS and mGPS may contribute to part of frailty and prognostic assessment in this patient cohort.

Evaluation of the prognostic value of computed tomography-derived body composition in patients undergoing endovascular aneurysm repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) is the most common mode of repair of abdominal aortic aneurysms (AAA) in the UK. EVAR ranges from standard infrarenal repair to complex fenestrated and branched EVAR (F/B-EVAR). Sarcopenia is defined by lower muscle mass and function, which is associated with inferior perioperative outcomes. Computed tomography-derived body composition analysis offers prognostic value in patients with cancer. Several authors have evaluated the role of body composition analysis in predicting outcomes in patients undergoing EVAR; however, the evidence base is limited by heterogeneous methodology. METHODS: Six hundred seventy-four consecutive patients (58 (8.6%) female, mean (SD) age 74.4 (6.8) years) undergoing EVAR and F/B-EVAR at three large tertiary centres were retrospectively recruited. Subcutaneous and visceral fat indices (SFI and VFI), psoas and skeletal muscle indices, and skeletal muscle density were measured at the L3 vertebral level from pre-operative computed tomographies. The maximally selected rank statistic technique was used to define optimal thresholds to predict mortality. RESULTS: There were 191 deaths during the median follow-up period of 60.0 months. Mean (95% CI) survival in the low SMI versus high SMI subgroups was 62.6 (58.5-66.7) versus 82.0 (78.7-85.3) months (P < 0.001). Mean (95% CI) survival in the low SFI versus high SFI subgroups was 56.4 (48.2-64.7) versus 77.1 (74.2-80.1) months (P < 0.001). One-year mortality in the low SMI versus high SMI subgroups was 10% versus 3% (P < 0.001). Low SMI was associated with increased odds of one-year mortality (OR 3.19, 95% CI 1.60-6.34, P < 0.001). Five-year mortality in the low SMI versus high SMI subgroups was 55% versus 28% (P < 0.001). Low SMI was associated with increased odds of five-year mortality (OR 1.54, 95% CI 1.11-2.14, P < 0.01). On multivariate analysis of all patients, low SFI (HR 1.90, 95% CI 1.30-2.76, P < 0.001) and low SMI (HR 1.88, 95% CI 1.34-2.63, P < 0.001) were associated with poorer survival. On multivariate analysis of asymptomatic AAA patients, low SFI (HR 1.54, 95% CI 1.01-2.35, P < 0.05) and low SMI (HR 1.71, 95% CI 1.20-2.42, P < 0.01) were associated with poorer survival. CONCLUSIONS: Low SMI and SFI are associated with poorer long-term survival following EVAR and F/B-EVAR. The relationship between body composition and prognosis requires further evaluation, and external validation of the thresholds proposed in patients with AAA is required.

Adverse Tumour and Host Biology May Explain the Poorer Outcomes Seen in Emergency Presentations of Colon Cancer.

OBJECTIVE: To examine the association between tumor/host factors (including the systemic inflammatory response), mode of presentation, and short/long-term outcomes in patients undergoing curative resectional surgery for TNM I to III colon cancer. BACKGROUND: Emergency presentations of colon cancer are associated with worse long-term outcomes than elective presentations despite adjustment for TNM stage. A number of differences in tumor and host factors have been identified between elective and emergency presentations and it may be these factors that are associated with adverse outcomes. METHODS: Patients undergoing curative surgery for TNM I to III colon cancer in the West of Scotland from 2011 to 2014 were identified. Tumor/host factors independently associated with the emergency presentation were identified and entered into a subsequent survival model to determine those that were independently associated with overall survival/cancer-specific survival (OS/CSS). RESULTS: A total of 2705 patients were identified. The emergency presentation was associated with a worse 3-year OS and CSS compared with elective presentations (70% vs 86% and 91% vs 75%). T stage, age, systemic inflammatory grade, anemia (all P < 0.001), N stage ( P = 0.077), extramural venous invasion ( P = 0.003), body mass index ( P = 0.001), and American Society of Anesthesiologists Classification classification ( P = 0.021) were independently associated with emergency presentation. Of these, body mass index [hazard ratio (HR), 0.82], American Society of Anesthesiologists Classification (HR, 1.45), anemia (HR, 1.29), systemic inflammatory grade (HR. 1.11), T stage (HR, 1.57), N stage (HR, 1.80), and adjuvant chemotherapy (HR, 0.47) were independently associated with OS. Similar results were observed for CSS. CONCLUSIONS: Within patients undergoing curative surgery for colon cancer, the emergency presentation was not independently associated with worse OS/CSS. Rather, a combination of tumor and host factors account for the worse outcomes observed.